p16INK4a is a beta-catenin target gene and indicates low survival in human colorectal tumors.
OBJECTIVE
Human colorectal carcinomas display an infiltrative front of invasion where tumor cells undergo an epithelomesenchymal transition associated with low survival. Epithelomesenchymal transition is regulated by a nuclear beta-catenin accumulation, and subsequently, activation of beta-catenin/TCF4 target genes similar to CYCLIN D(1). Unexpectedly, these tumor cells are characterized by low proliferation, which correlates with the expression of the cell cycle inhibitor p16(INK4A). Therefore, we investigated the molecular mechanism of the transcriptional regulation of p16(INK4A) in colorectal cancer and its correlation with survival.


METHODS
Molecular biological techniques were used for investigating the transcriptional mechanisms of the p16(INK4A) gene regulation. Moreover, p16(INK4A) expression was correlated with the 10-year survival of patients with colorectal carcinomas.


RESULTS
In colorectal carcinomas, expression of the p16(INK4A) gene is regulated by beta-catenin/TCF4 and correlates with low survival rates of patients with tumors displaying an infiltrative front of invasion.


CONCLUSIONS
beta-catenin/TCF4 regulates cell cycle promoting (c-MYC, CYCLIN D(1)) and inhibiting genes (p16(INK4A)) at the same time in the mesenchymally differentiated tumor cells at the front of invasion. The function of p16(INK4A) seems to supersede in this context thus leading to low proliferation. Moreover, these tumor cells seem to govern the outcome of colorectal cancer independently of their proliferation.
Wassermann
Stella
S
Pathologisch-Anatomisches Institut der Universität Erlangen-Nürnberg, Erlangen, Germany.
Scheel
Silvio K
SK
Hiendlmeyer
Elke
E
Palmqvist
Richard
R
Horst
David
D
Hlubek
Falk
F
Haynl
Angela
A
Kriegl
Lydia
L
Reu
Simone
S
Merkel
Susanne
S
Brabletz
Thomas
T
Kirchner
Thomas
T
Jung
Andreas
A
D000328:Adult; D000368:Aged; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005260:Female; D005786:Gene Expression Regulation; D019942:Genes, p16; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism; D051176:beta Catenin / Q000502:physiology*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin